The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments (see, e.g., Drugs Fut. 1996; 21: 507-20; Progress in Drug Research 1995; 45: 107-65). Recently, the human histamine H3 receptor has been cloned, cf. Molecular Pharmacology, 1999; 55: 1101-7. The histamine H3 receptor is a presynaptic autoreceptor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (i.e., it is active in the absence of an agonist; see, e.g., Nature 2000; 408: 860-4). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Some of these are imidazole derivatives (see, e.g., Drugs Fut 1996; 21: 507-20; Expert Opinion on Therapeutic Patents 2000; 10: 1045-55). However, a variety of imidazole-free ligands of the histamine H3 receptor is also described (see, e.g., Arch Pharm Pharm Med Chem 1999; 332: 389-98; J Med Chem 2000; 43: 2362-70; Arch Pharm Pharm Med Chem 1998; 331: 395-404; II Farmaco 1999; 54: 684-94; WO 99/42458, EP 0 978 512, WO 97/17345, U.S. Pat. No. 6,316,475, WO 01/66534, WO 01/74810, WO 01/44191, WO 01/74815, WO 01/74773, WO 01/74813, WO 01/74814 and WO 02/12190). The state of the art is also reviewed in Drug Discovery Today, 2005; 10: 1613-17 and Nat Rev Drug Discov 2005; 4: 107. In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of substituted benzothiazoles and benzoxazoles has a high and specific affinity to and potency at the histamine H3 receptor.
Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endo-crinological system.
In U.S. Pat. No. 6,130,217, column 120, example 85, the intermediate 2-(4-methylpiperazin-1-yl)benzothiazol-7-ol is mentioned. No pharmacological properties are mentioned for this compound.
In JP 11199573, the following compounds are mentioned: 2-(piperazin-1-yl)-6-chlorobenzothiazole fumarate; 2-(piperazin-1-yl)-5-chlorobenzothiazole fumarate; 2-(4-methylpiperazin-1-yl)-5-methylbenzothiazole fumarate; 2-(piperazin-1-yl)-5-methylbenzo-thiazole fumarate; 2-(4-methylpiperazin-1-yl)-6-chlorobenzothiazole fumarate and 2-(4-methylpiperazin-1-yl)-5-chlorobenzothiazole dihydrochloride.
In JP 2869561, the following compounds are mentioned: 2-(piperazin-1-yl)-6-chloro-benzothiazole and 2-(piperazin-1-yl)-6-(o-chlorobenzylamino)benzothiazole hydrochloride. It is stated that the compounds are platelet adhesion inhibitors.
In JP 4316565, the following intermediates are mentioned: 2-(4-methylpiperazin-1-yl)-6-methoxybenzothiazole and 2-(4-methylpiperazin-1-yl)-6-hydroxybenzothiazole. No pharmacological properties are mentioned for these compounds.
The object of this invention is to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.